1. Field of the Invention
The invention relates to pharmaceutical compositions for preventing or treating bone formation-relating diseases, particularly fractures.
2. Description of the Prior Art
Bones maintain a supporting function as endoskeleton by repeated local bone resorption and bone formation to substitute old bones with new ones and they also prepare for a rapid reactivity to various mechanical stresses and changes in mineral balance. This osteoanagenesis is performed mainly by bone resorption cells such as osteoclasts and the like and bone formation cells such as osteoblasts and the like, based upon coupling of both cells. Recently, osteoblasts have been reported not only to have the function of bone formation, but to closely relate to differentiation and activation of osteoclasts, so that there may be an increased possibility of playing a role as a controlling center in cellular bone reconstruction [Inoue, T., Mebio (1990), Special Version p. 2-7].
The plate let factor 4 (PF4) is the protein which is characteristic of platelet and may be specifically bound to heparin to neutralize the anticoagulant activity of heparin. And further, it is known that PF4 may act as a chemotactic factor on leukocytes, monocytes and fibroblasts and show an anti-collagenase activity for protecting tissues from impairment caused by the collagenase released from leukocytes (polynuclear neutrophils) in inflammatory lesions. It was also elucidated that human PF4 blocked reversibly parathyroid hormone (PTH)-stimulated .sup.45 Ca.sup.2+ release from newborn rat bone in vitro [Horton, J. E., et al., Biochem. Biophys, Acta. (1980), Vol. 630, p. 459-462]. Recently, human PF4 has been found to inhibit human osteosarcoma cell lines Saos-2 and G-292 proliferation, from which the antitumor effect is expected [Tatakis, D. N., Biochem. Biophys. Res. Commun. (1992), Vol. 187, p. 287-293].
Human PF4 was found to be composed of 70 amino acids and bovine PF4 was found to be the polypeptide composed of 88 amino acids, while the respective sequences were determined [Hermodson, M., et al., J. Biol. Chem. (1977), Vol. 252, p. 6276-6278; Ciaglowski, R. E., et al., Arch. Biochem. Biophys. (1986), .Vol. 250, p. 249-256].
PF4 is released from platelets in the binding form with proteoglycan, but it is believed that proteoglycan may be replaced with heparin. Recently, there has been investigated determination of PF4 values in plasma by radioimmunoassay. PF4 activity has been abundantly detected in the fraction containing .alpha.-granules which were isolated by the intracellular organella fractionation method. And further, PF4 was detected in platelets and megakaryocytes by immunofluorescence microscopy technique, while its synthesis in megakaryocytes was assumed [Ginsberg, M. H., et al., Blood (1980), Vol. 55, p. 661-668; Ryo, R., et al., Thromb. Res. (1980), Vol. 17, p. 645-652].
On the other hand, it is known that a variety of bone formation factors may participate in the course of bone formation [Noda, M., BIOmedica (1993), Vol. 8, p. 28-33]. In particular, it is known that estrogen, PTH and anabolic hormone may promote bone formation. Although PF4 is known to inhibit bone resorption (Horton, J. E., et al., loc. cit.) , no report has suggested that PF4 may be also effective in bone formation.